US5948795A - Benzothiopene compounds, and uses and formulations thereof - Google Patents
Benzothiopene compounds, and uses and formulations thereof Download PDFInfo
- Publication number
- US5948795A US5948795A US08/882,711 US88271197A US5948795A US 5948795 A US5948795 A US 5948795A US 88271197 A US88271197 A US 88271197A US 5948795 A US5948795 A US 5948795A
- Authority
- US
- United States
- Prior art keywords
- phenyl
- compound
- formula
- pai
- piperidinyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D333/66—Nitrogen atoms not forming part of a nitro radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/56—Radicals substituted by oxygen atoms
Definitions
- PAI-1 plasminogen activator inhibitor I
- tPA tissue type plasminogen activator
- PAI-1 can be produced in a variety of tissues, substantial levels are secreted by the vascular endothelial cell.
- the vascular endothelium constitutes a major organ that functions in the regulation of blood coagulation, inflammation and in the exchange of fluids and mediators between the intravascular compartment and parenchyma tissues. As such, the proper function of the endothelium is critical to overall homeostasis.
- PAI-1 can be increased in endothelial cells in response to certain stimuli, including cytokines, it contributes to a dysfunctional state that can result in coagulation defects, local and systemic vascular inflammation, and enhancement in the progression and rupture of atherosclerotic plaque. These effects can further result in conditions including myocardial infarction, deep venous thrombosis, and disseminated intravascular thrombosis.
- agents that inhibit the expression of PAI-1 in the endothelium could be useful in treating or preventing conditions such as sepsis, injuries involving major tissue damage and trauma, systemic inflammatory response syndrome, sepsis syndrome, septic shock and multiple organ dysfunction syndrome (including DIC) as well as myocardial infarction, deep venous thrombosis, disseminated intravascular thrombosis, atherosclerotic plaque rupture and its associated sequela.
- tPA tissue Plasiminogen Activator
- Exogenously administered tPA has been shown to be effective and is commercially available for treatment of such patients.
- efficacy of this therapy can be limited because PAI-1 inhibits the exogenously given tPA as well as the endogenously derived tPA. Therefore, it would be of great value if an agent were available which could either prolong the half-life or reduce the amount of exogenously administered tPA.
- agents that modulate PAI-1 may find use as anti-metastatic agents.
- This invention provides compounds of formula I ##STR2## wherein R 1 , R 2 , and R 3 are independently --OH, --OCO(C 1 -C 6 alkyl), --O(CO)O(C 1 -C 6 alkyl), --OCO--Ar, where Ar is phenyl or substituted phenyl, or --O(CO)O--phenyl; and
- R 4 is N-pyrrolidinyl, N-piperidinyl, or N-hexamethyleneimino; or a pharmaceutically acceptable salt or solvate thereof.
- the present invention relates to methods of using the compounds of formula I in inhibiting PAI-1.
- the present invention also relates to pharmaceutical formulations containing compounds of formula I.
- the current invention concerns the discovery of a select group of novel 2-phenyl-3-aroyl-benzo b!thiophenes, those of formula I, and their use for inhibiting PAI-1.
- the methods of use provided by this invention are practiced by administering to a human in need thereof a dose of a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, that is effective to inhibit PAI-1 or a physiological condition associated with an excess or undesirable activity thereof.
- the term "inhibit” includes its generally accepted meaning which includes prohibiting, preventing, restraining, and slowing, stopping, or reversing progression, severity, or ameliorating a resultant symptom or effect.
- C 1 -C 6 alkyl refers to straight or branched aliphatic chains of 1 to 6 carbon atoms including methyl, ethyl, propyl, iso-propyl, n-butyl, pentyl, iso-pentyl, hexyl, and the like.
- substituted phenyl refers to a phenyl group having one or more substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 alkoxy, hydroxy, nitro, chloro, fluoro, or tri(chloro or fluoro)methyl.
- C 1 -C 3 alkoxy refers a C 1 -C 3 alkyl group attached through an oxygen bridge such as methoxy, ethoxy, n-propoxy, iso-propoxy.
- a preferred embodiment of this invention is 4,6-dihydroxy-2-(4-hydroxyphenyl)benzo b!thien-3-yl! 4- 2-(1-piperidinyl)ethoxy!phenyl!methanone dihydrate.
- the 4,6-dialkoxy benzo b!thiophene as its 2-dialkylamino derivative (formula II) where R 5 and R 6 are independently C 1 -C 6 alkyl, is prepared by the cyclisation of 2-(2,4-dialkylphenyl)-2-hydroxy-N,N-dialkylthioacetamide with a strong acid catalyst, such as methansulfonic acid, at ambient or elevated temperature, approximately 25° to 150° C., in an inert solvent, such as dichloroethane or the like. This reaction is exemplified in Preparation 2.
- the thioacetamide may be prepared from the condensation of 2,4-dialkoxybenzaldehyde with N,N-dialkylthioformate, preferred would N,N-dimethylthioformate, and lithium diisopropylamide (LDA) at low temperature, approximately -80° to -50° C., and in an inert solvent such as hexane. This reaction is exemplified in Preparation 1.
- the 3-aroyl function bearing the nitrogen-containing side-chain is introduced into an intermediate molecule (formula IV) by reacting 2-(2,4-dialkoxyphenyl)-2-hydroxy-N,N-dialkylthioacetamide with a compound of formula III at elevated temperature (50° to 150° C.) in an appropriate solvent such as toluene, chlorobenzene, or the like.
- the carbonyl activating moiety of compound III, (X) may be chloro, bromo, a mixed anhydride, or the like.
- the preferred carbonyl activity moiety is chloro.
- Compounds of formula III may be facily prepared by methods known in the art such as in U.S. Pat. No. 4,133,814, incorporated herein by reference. An example of this synthesis is illustrated in Preparation 3.
- the 2-phenylalkoxy derivative (formula V) is prepared from a compound of formula IV by reaction with 4-alkoxyphenylmagnesium bromide (Grignard reagent) in an inert solvent such as THF, ether, or CH 2 Cl 2 , at a temperature in the range of 0° to 50° C.
- An illustration of this reaction is given in Preparation 4.
- a compound of formula Ia: ##STR7## may be prepared by de-protecting (de-alkoxylating) a compound of formula V. Such deprotection methods are taught in the U.S. patent reference, supra, or illustrated in Example 1, below.
- the compounds of formula I may also be prepared by variations of other routes (see: Jones, C. D., et al., J. Med. Chem.,1984,27,p. 1057), those routes and appropriate modifications would be apparent and known to those of ordinary skill in the art of organic chemistry.
- This reaction sequence begins with the S-alkylation of a thiophenol (VI) with a substituted phenacyl bromide (VII).
- Preferred substrates for these reactions would the compounds where (C 1 -C 6 alkyl)O is CH 3 O--.
- This reaction is run in the presence of a strong base such as K 2 CO 3 , Na 2 CO 3 , and the like, in inert solvents such as THF, DMF, ether, etc.
- a strong base such as K 2 CO 3 , Na 2 CO 3 , and the like
- inert solvents such as THF, DMF, ether, etc.
- a preferred temperature would be the reflux temperature of a preferred solvent such as DMF.
- the reaction is usually complete within one to six hours.
- the arylthioether (VIII) is converted to the benzo b!thiophene (IX) by an acid catalysed, thermal rearrangement.
- This reaction is usually carried in a high boiling solvent such diphenyl ether, halobenzene, xylenes, etc., preferred would be xylene.
- the strong acid may be toluenesulfonic acid, sulfuric acid, etc., preferred would be poly-phosphoric acid.
- the reaction is carried out at about 120° C. and is complete within six to eighteen hours.
- the compounds of formula IX may be acylated at the 3-position of the benzothiophene nucleus with an activated carboxyl moieties of a compound of formula III under standard Friedel-Crafts conditions.
- the acylating conditions would be the use of a Lewis acid such as, AlCl 3 , BF 3 , and the like, in an appropriate solvent such as a halogenated hydrocarbon, at temperatures from 0-100° C.
- the activated carboxyl moieties of the compounds of formula III are acyl halides, mixed anhydrides, and the like, preferred would be the acid chloride. This acylation yields the compounds of formula V.
- a mono-, di-, or trihydroxy compound of formula I is reacted with an agent such as acyl chloride, bromide, cyanide, or azide, or with an appropriate anhydride or mixed anhydride.
- an agent such as acyl chloride, bromide, cyanide, or azide
- the reactions are conveniently carried out in a basic solvent such as pyridine, lutidine, quinoline or isoquinoline, or in a tertiary amine solvent such as triethylamine, tributylamine, methylpiperidine, and the like.
- the reaction also may be carried out in an inert solvent such as ethyl acetate, dimethylformamide, dimethylsulfoxide, dioxane, dimethoxyethane, acetonitrile, acetone, methyl ethyl ketone, and the like, to which at least one equivalent of an acid scavenger (except as noted below), such as a tertiary amine, has been added.
- an acid scavenger except as a tertiary amine
- acylation catalysts such as 4-dimethylaminopyridine or 4-pyrrolidinopyridine may be used. See, e.g., Haslam, et al., Tetrahedron, 36:2409-2433 (1980).
- the present reactions are carried out at moderate temperatures, in the range from about -25° C. to about 100° C., frequently under an inert atmosphere such as nitrogen gas. However, ambient temperature is usually adequate for the reaction to run.
- Acylation of a 6-, -4 and/or -4'-position hydroxy group also may be performed by acid-catalyzed reactions of the appropriate carboxylic acids in inert organic solvents.
- Acid catalysts such as sulfuric acid, polyphosphoric acid, methanesulfonic acid, and the like are used.
- R 1 , R 2 and/or R 3 groups of formula I compounds also may be provided by forming an active ester of the appropriate acid, such as the esters formed by such known reagents such as dicyclohexylcarbodiimide(DCC), acylimidazoles, nitrophenols, pentachlorophenol, N-hydroxysuccinimide, and 1-hydroxybenzotriazole.
- DCC dicyclohexylcarbodiimide
- acylimidazoles nitrophenols
- pentachlorophenol pentachlorophenol
- N-hydroxysuccinimide and 1-hydroxybenzotriazole.
- a 110 mL THF solution of lithium diisopropylamide (LDA) ( 80 mmol) was generated from a 1.6 M hexane solution of n-butyllithium (50 mL, 80 mmol) and diisopropylamine ( 11.2 mL, 80 mmol) at -10° C., then cooled to -78° C.
- a 50 mL solution of 2,4-dimethoxybenzaldehyde (12 g, 72 mmol) and N,N-dimethylthioformamide (6.8 mL, 80 mmol) was cooled to 0° C. and added to the -78° C. LDA solution at a rate keeping the temperature less than -70° C.
- reaction mixture was stirred at -75° C. for 2.5 hours, allowed to warm to 0° C., quenched with saturated aqueous NH 4 Cl, and extracted with EtOAc three times. The EtOAc extracts were combined, washed with brine, dried (Na 2 SO 4 ), concentrated, triturated with Et 2 O/ pet.
- Methanesulfonic acid (2.8 mL, 20 mmol) was added portionwise to a 150 mL CH 2 Cl 2 solution of N,N-dimethyl-2-(4,6-dimethoxyphenyl)-2-hydroxythioacetamide (2.5 g, 10 mmol) and stirred at ambient temperature for 2 hours.
- the reaction mixture was poured into saturated aqueous NaHCO 3 /ice, extracted with CH 2 Cl 2 , the CH 2 Cl 2 extracts combined, washed with brine, dried (Na 2 SO 4 ), and concentrated.
- the compounds used in the methods of this invention form pharmaceutically acceptable acid salts with a wide variety of organic and inorganic acids and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention.
- Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric and the like.
- Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, ⁇ -hydroxybutyrate, butyne-1,4-dioate, hexyne-1,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, teraphthalate, phosphate, monohydrogenphosphat
- the pharmaceutically acceptable acid addition salts are typically formed by reacting a compound of formula I with an equimolar or excess amount of acid.
- the reactants are generally combined in a mutual solvent such as diethyl ether or benzene.
- the salt normally precipitates out of solution within about one hour to 10 days and can be isolated by filtration or the solvent can be stripped off by conventional means.
- the pharmaceutically acceptable salts generally have enhanced solubility characteristics compared to the compound from which they are derived, and thus are often more amenable to formulation as liquids or emulsions.
- compositions can be prepared by procedures known in the art.
- the compounds can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, suspensions, powders, and the like.
- excipients, diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate, and solid
- the compounds can also be formulated as elixirs or solutions for convenient oral administration or as solutions appropriate for parenteral administration, for instance by intramuscular, subcutaneous or intravenous routes. Additionally, the compounds are well suited to formulation as sustained release dosage forms and the like.
- the formulations can be so constituted that they release the active ingredient only or preferably in a particular part of the intestinal tract, possibly over a period of time.
- the coatings, envelopes, and protective matrices may be made, for example, from polymeric substances or waxes.
- a compound of formula I required to inhibit PAI-1, or any other use disclosed herein, and according to this invention will depend upon the severity of the condition, the route of administration, and related factors that will be decided by the attending physician. Generally, accepted and effective daily doses will be from about 0.1 to about 1000 mg/day, and more typically from about 50 to about 200 mg/day. Such dosages will be administered to a subject in need thereof from once to about three times each day, or more often as needed to effectively inhibit PAI-1, or any other use disclosed herein.
- Active ingredient means a compound of formula I.
- the ingredients are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules.
- a tablet formulation is prepared using the ingredients below:
- the components are blended and compressed to form tablets.
- tablets each containing 0.1-1000 mg of active ingredient are made up as follows:
- the active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
- the solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve.
- the granules so produced are dried at 50°-60° C. and passed through a No. 18 mesh U.S. sieve.
- the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 60 U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets.
- the medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste.
- the benzoic acid solution, flavor, and color are diluted with some of the water and added, with stirring. Sufficient water is then added to produce the required volume.
- 96 well tissue culture plates were prepared with 1 ⁇ 10 4 human endothelial cells (HUVEC) per well in Clonetics' Endothelial Cell Growth Medium (EGM) supplemented with 2% FBS. Following incubation overnight at 37 -- C., the medium was replaced with serum-free medium (DMEM/F-12 medium, 20 mM-HEPES, pH 7.5, 50 ⁇ g/ml gentamicin, 1 ⁇ g/ml human transferrin and 1 ⁇ g/ml bovine insulin) with or without compound 1, (where R 1 , R 2 , and R 3 are hydroxy, and R 4 is piperidinyl), and with or without 1 nM IL-1-beta. Following incubation overnight at 37 -- C., samples of culture medium were assayed for secreted PAI-1 using the Imubind Plasma PAI-1 ELISA (American Diagnostic Inc. #822/1S).
- Imubind Plasma PAI-1 ELISA American Diagnostic Inc. #822/1S.
- Human umbilical vein endothelial cells were treated with compound 1 (Example I) concurrent to the induction of PAI-1 with IL-1.
- compound 1 Example I
- Table 1 In initial experiments with several lots of cells obtained from a commercial supplier (Clonetics), we found that not all lots were responsive to 17-beta estradiol, and were thus not used in experiments to determine the effect of compound 1 on PAI-1 secretion.
- Table 1 using an estrogen-responsive line, we observed Compound 1 significantly reduced the induction of PAI-1 by IL-1 at a concentration of 1 nM.
- compound 1 is a potent inhibitor of the induction of PAI-1 from activated endothelial cells and should result in a cardioprotective effect, i.e. reduction in the incidence of cardiovascular events, due to enhancing fibrinolytic potential.
- the positive effect of compound 1 on reducing PAI-1 may provide for acute and chronic uses in conditions where elevated levels are associated with pathology or may be used to prevent such pathological conditions.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/882,711 US5948795A (en) | 1996-07-15 | 1997-06-25 | Benzothiopene compounds, and uses and formulations thereof |
US09/089,521 US5962698A (en) | 1996-07-15 | 1998-06-03 | Benzothiophene compounds, and uses and formulations thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US2178896P | 1996-07-15 | 1996-07-15 | |
US08/882,711 US5948795A (en) | 1996-07-15 | 1997-06-25 | Benzothiopene compounds, and uses and formulations thereof |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/089,521 Division US5962698A (en) | 1996-07-15 | 1998-06-03 | Benzothiophene compounds, and uses and formulations thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
US5948795A true US5948795A (en) | 1999-09-07 |
Family
ID=21806155
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/882,711 Expired - Fee Related US5948795A (en) | 1996-07-15 | 1997-06-25 | Benzothiopene compounds, and uses and formulations thereof |
US09/089,521 Expired - Fee Related US5962698A (en) | 1996-07-15 | 1998-06-03 | Benzothiophene compounds, and uses and formulations thereof |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US09/089,521 Expired - Fee Related US5962698A (en) | 1996-07-15 | 1998-06-03 | Benzothiophene compounds, and uses and formulations thereof |
Country Status (10)
Country | Link |
---|---|
US (2) | US5948795A (fr) |
EP (1) | EP0819687B1 (fr) |
JP (1) | JPH1067774A (fr) |
AT (1) | ATE199717T1 (fr) |
CA (1) | CA2207141A1 (fr) |
DE (1) | DE69704235T2 (fr) |
DK (1) | DK0819687T3 (fr) |
ES (1) | ES2155655T3 (fr) |
GR (1) | GR3035981T3 (fr) |
PT (1) | PT819687E (fr) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003000671A1 (fr) * | 2001-06-20 | 2003-01-03 | Wyeth | Derives du naphthyl benzofurane inhibiteurs de l'inhibiteur 1 de l'activateur du plasminogene (pai-1) |
US20040132770A1 (en) * | 2001-05-22 | 2004-07-08 | Wallace Owen Brendan | Tetrahydroquinolin derivatives for the inhibition of diseases associated with estrogen deprivation or with an aberrant physiological response to endogenous estrogen |
US20040215018A1 (en) * | 2001-05-22 | 2004-10-28 | Wallace Owen Brendan | 2-substituted 1,2,3,4-tetrahydroquinolines and derivatives thereof, compositions and methods |
US20050070587A1 (en) * | 2003-09-25 | 2005-03-31 | Wyeth | Substituted naphthyl benzothiophene acids |
US20050119296A1 (en) * | 2003-09-25 | 2005-06-02 | Wyeth | Substituted heteroaryl benzofuran acids |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI224101B (en) * | 2001-06-20 | 2004-11-21 | Wyeth Corp | Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1) |
ATE370941T1 (de) * | 2003-11-20 | 2007-09-15 | Lilly Co Eli | Modulatoren des vitamin-d-rezeptors |
Citations (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3594478A (en) * | 1965-06-01 | 1971-07-20 | Haessle Ab | Pharmaceutical compositions containing benzothiophene derivatives |
US3598839A (en) * | 1969-06-30 | 1971-08-10 | Parke Davis & Co | Phenylbenzothiophene compounds |
US3935231A (en) * | 1972-10-17 | 1976-01-27 | Sandoz Ltd., (Sandoz Ag) | Novel benzothiophene derivatives as stabilizers for organic compounds |
FR2329271A1 (fr) * | 1975-10-28 | 1977-05-27 | Lilly Co Eli | Nouveaux agents anti-fertilite |
EP0062503A1 (fr) * | 1981-04-03 | 1982-10-13 | Eli Lilly And Company | Dérivés de benzothiophène et procédé pour les préparer |
US4418068A (en) * | 1981-04-03 | 1983-11-29 | Eli Lilly And Company | Antiestrogenic and antiandrugenic benzothiophenes |
US4654352A (en) * | 1984-07-10 | 1987-03-31 | Pfizer Inc. | Method for treating diarrhea with benzothiophene derivatives |
US5175184A (en) * | 1982-10-19 | 1992-12-29 | Kotobuki Seiyaku Company Limited | Benzothiophene derivatives and antihyperuricemia thereof |
US5254594A (en) * | 1991-04-09 | 1993-10-19 | Klinge Pharma Gmbh | Remedies for bone diseases |
EP0641791A1 (fr) * | 1991-11-15 | 1995-03-08 | Teikoku Hormone Mfg. Co., Ltd. | Nouveau derive de benzothiophene |
WO1995034557A1 (fr) * | 1994-06-10 | 1995-12-21 | Eli Lilly And Company | 2-AMINO-3-AROYL-BENZO[β]THIOPHENES ET PROCEDE DE PRODUCTION DE CES COMPOSES |
US5532382A (en) * | 1995-03-13 | 1996-07-02 | Eli Lilly And Company | Benzothiophenes substituted at the 3-carbonyl |
US5595722A (en) * | 1993-01-28 | 1997-01-21 | Neorx Corporation | Method for identifying an agent which increases TGF-beta levels |
WO1997013511A1 (fr) * | 1995-10-10 | 1997-04-17 | Eli Lilly And Company | Procede d'inhibiton de l'inhibiteur 1 d'activiteur de plasminogene |
-
1997
- 1997-06-05 CA CA002207141A patent/CA2207141A1/fr not_active Abandoned
- 1997-06-25 US US08/882,711 patent/US5948795A/en not_active Expired - Fee Related
- 1997-07-11 PT PT97305119T patent/PT819687E/pt unknown
- 1997-07-11 DE DE69704235T patent/DE69704235T2/de not_active Expired - Fee Related
- 1997-07-11 EP EP97305119A patent/EP0819687B1/fr not_active Expired - Lifetime
- 1997-07-11 ES ES97305119T patent/ES2155655T3/es not_active Expired - Lifetime
- 1997-07-11 DK DK97305119T patent/DK0819687T3/da active
- 1997-07-11 AT AT97305119T patent/ATE199717T1/de not_active IP Right Cessation
- 1997-07-14 JP JP9188233A patent/JPH1067774A/ja not_active Withdrawn
-
1998
- 1998-06-03 US US09/089,521 patent/US5962698A/en not_active Expired - Fee Related
-
2001
- 2001-05-31 GR GR20010400832T patent/GR3035981T3/el not_active IP Right Cessation
Patent Citations (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3594478A (en) * | 1965-06-01 | 1971-07-20 | Haessle Ab | Pharmaceutical compositions containing benzothiophene derivatives |
US3598839A (en) * | 1969-06-30 | 1971-08-10 | Parke Davis & Co | Phenylbenzothiophene compounds |
US3935231A (en) * | 1972-10-17 | 1976-01-27 | Sandoz Ltd., (Sandoz Ag) | Novel benzothiophene derivatives as stabilizers for organic compounds |
FR2329271A1 (fr) * | 1975-10-28 | 1977-05-27 | Lilly Co Eli | Nouveaux agents anti-fertilite |
US4133814A (en) * | 1975-10-28 | 1979-01-09 | Eli Lilly And Company | 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents |
EP0062503A1 (fr) * | 1981-04-03 | 1982-10-13 | Eli Lilly And Company | Dérivés de benzothiophène et procédé pour les préparer |
US4418068A (en) * | 1981-04-03 | 1983-11-29 | Eli Lilly And Company | Antiestrogenic and antiandrugenic benzothiophenes |
US5175184A (en) * | 1982-10-19 | 1992-12-29 | Kotobuki Seiyaku Company Limited | Benzothiophene derivatives and antihyperuricemia thereof |
US4654352A (en) * | 1984-07-10 | 1987-03-31 | Pfizer Inc. | Method for treating diarrhea with benzothiophene derivatives |
US5254594A (en) * | 1991-04-09 | 1993-10-19 | Klinge Pharma Gmbh | Remedies for bone diseases |
EP0641791A1 (fr) * | 1991-11-15 | 1995-03-08 | Teikoku Hormone Mfg. Co., Ltd. | Nouveau derive de benzothiophene |
US5472962A (en) * | 1991-11-15 | 1995-12-05 | Teikoku Hormone Mfg. Co., Ltd. | Benzothiophene derivative |
US5595722A (en) * | 1993-01-28 | 1997-01-21 | Neorx Corporation | Method for identifying an agent which increases TGF-beta levels |
WO1995034557A1 (fr) * | 1994-06-10 | 1995-12-21 | Eli Lilly And Company | 2-AMINO-3-AROYL-BENZO[β]THIOPHENES ET PROCEDE DE PRODUCTION DE CES COMPOSES |
US5532382A (en) * | 1995-03-13 | 1996-07-02 | Eli Lilly And Company | Benzothiophenes substituted at the 3-carbonyl |
WO1997013511A1 (fr) * | 1995-10-10 | 1997-04-17 | Eli Lilly And Company | Procede d'inhibiton de l'inhibiteur 1 d'activiteur de plasminogene |
Non-Patent Citations (6)
Title |
---|
Chemical Abstracts , vol. 115, No. 5 (Aug. 5, 1991. * |
Chemical Abstracts , vol. III, No. 9 (Aug. 28, 1989). * |
Chemical Abstracts, vol. 115, No. 5 (Aug. 5, 1991. |
Chemical Abstracts, vol. III, No. 9 (Aug. 28, 1989). |
von Agerer E and Erber S. J. Steroid Biochem. Mol. Biol. 41, 557 562, 1992. * |
von Agerer E and Erber S. J. Steroid Biochem. Mol. Biol. 41, 557-562, 1992. |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040132770A1 (en) * | 2001-05-22 | 2004-07-08 | Wallace Owen Brendan | Tetrahydroquinolin derivatives for the inhibition of diseases associated with estrogen deprivation or with an aberrant physiological response to endogenous estrogen |
US20040215018A1 (en) * | 2001-05-22 | 2004-10-28 | Wallace Owen Brendan | 2-substituted 1,2,3,4-tetrahydroquinolines and derivatives thereof, compositions and methods |
US6962928B2 (en) | 2001-05-22 | 2005-11-08 | Eli Lilly And Company | Tetrahydroquinoline derivatives for the inhibition of osteoporosis, estrogen dependent breast cancer, endometriosis and uterine fibrosis |
US7056931B2 (en) | 2001-05-22 | 2006-06-06 | Eli Lilly And Company | 2-substituted 1,2,3,4-tetrahydroquinolines and derivatives thereof, compositions and methods |
WO2003000671A1 (fr) * | 2001-06-20 | 2003-01-03 | Wyeth | Derives du naphthyl benzofurane inhibiteurs de l'inhibiteur 1 de l'activateur du plasminogene (pai-1) |
US6599925B2 (en) | 2001-06-20 | 2003-07-29 | Wyeth | Substituted naphthyl benzofuran derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) |
US20050070587A1 (en) * | 2003-09-25 | 2005-03-31 | Wyeth | Substituted naphthyl benzothiophene acids |
US20050119296A1 (en) * | 2003-09-25 | 2005-06-02 | Wyeth | Substituted heteroaryl benzofuran acids |
US7163954B2 (en) | 2003-09-25 | 2007-01-16 | Wyeth | Substituted naphthyl benzothiophene acids |
US7446201B2 (en) | 2003-09-25 | 2008-11-04 | Wyeth | Substituted heteroaryl benzofuran acids |
US20090054484A1 (en) * | 2003-09-25 | 2009-02-26 | Wyeth | Substituted heteroaryl benzofuran acids |
Also Published As
Publication number | Publication date |
---|---|
DK0819687T3 (da) | 2001-04-17 |
ES2155655T3 (es) | 2001-05-16 |
GR3035981T3 (en) | 2001-08-31 |
EP0819687A1 (fr) | 1998-01-21 |
US5962698A (en) | 1999-10-05 |
EP0819687B1 (fr) | 2001-03-14 |
JPH1067774A (ja) | 1998-03-10 |
DE69704235D1 (de) | 2001-04-19 |
CA2207141A1 (fr) | 1998-01-15 |
ATE199717T1 (de) | 2001-03-15 |
PT819687E (pt) | 2001-06-29 |
DE69704235T2 (de) | 2001-09-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6399634B1 (en) | Benzothiophene compounds, compositions, and methods | |
US5510498A (en) | Benzothiophene compounds, intermediates, compositions, and methods | |
US5780648A (en) | Benzothiophene compounds, and uses formulations thereof | |
US5948795A (en) | Benzothiopene compounds, and uses and formulations thereof | |
EP0747376B1 (fr) | Composés avec des chaînes latérales contenant de l'azote non-basiques et compositions les contenant | |
US5843963A (en) | Benzothiophene compounds, intermediates, processes, compositions, and methods | |
US6156786A (en) | 2-aryl-3-aroylbenzo[b]thiophenes useful for the treatment of estrogen deprivation syndrome | |
US5811437A (en) | Methods of increasing nitric oxide synthesis | |
EP0905132B1 (fr) | Benzothiophènes | |
JPH08333366A (ja) | 窒素含有非塩基性側鎖を有する化合物および医薬組成物 | |
EA000767B1 (ru) | Бензотиофены, составы, их содержащие, и способы с их использованием | |
US5731328A (en) | Methods of inhibiting plasminogen activator inhibitor 1 | |
US6090843A (en) | Benzothiophenes compounds which have useful pharmaceutical activity | |
US5688796A (en) | Heterocyclic substituted benzothiophenes, compositions, and methods | |
US6060488A (en) | Benzothiophenes for treating estrogen deficiency | |
EP0835872B1 (fr) | Dérivés de benzo(b)thiophène, produits intermédiaires, préparations et méthodes | |
EP0835871B1 (fr) | Dérivés de benzo(b)thiophène, produits intermédiaires, préparations et méthodes | |
US6017914A (en) | Benzo[b]thiophene compounds, intermediates, formulations, and methods | |
US5958969A (en) | Benzo b!thiophene compounds, intermediates, formulations, and methods | |
US6608090B1 (en) | Benzothiophenes with novel basic side chains | |
EP0707852A2 (fr) | Antagonistes bicycliques des récepteurs de la bradykinine | |
MXPA98002759A (en) | Methods to inhibit plasminog activator 1 inhibitor | |
MXPA98009706A (es) | Metodos para incrementar la sintesis de oxido nitrico |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: ELI LILLY AND COMPANY, INDIANA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BERG, DAVID THOMPSON;CULLINAN, GEORGE JOSEPH;GRINNEL, BRIAN WILLIAM;AND OTHERS;REEL/FRAME:010031/0582 Effective date: 19970513 |
|
FPAY | Fee payment |
Year of fee payment: 4 |
|
REMI | Maintenance fee reminder mailed | ||
LAPS | Lapse for failure to pay maintenance fees | ||
STCH | Information on status: patent discontinuation |
Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362 |
|
FP | Lapsed due to failure to pay maintenance fee |
Effective date: 20070907 |